Because hydrolytic degradation destroys the biological effectiveness of ingested peptide hormones, insulin in diabetes must be given parenterally. This project will investigate in animal models the biological effects of orally administered insulin entrapped in liposomes, synthetic microscopic aggregates of lipids arranged in a lamellar fashion about a series of aqueous layers containing the hormone. The effects of lipid composition and size of particles upon the kinetics of insulin appearance, and glucose concentration in the plasma of streptozotocin-induced diabetic rats will be investigated. At least 5 different lipids will be employed to produce liposomes in order to determine optimal composition; some 6 different sized particles will be produced to assess optimal size. The incorporation of insulin in liposomes will be quantified through radioimmunoassay of solubilized liposomes, and through incorporation of 125I-insulin into the particles during manufacture. The route of absorption will be quantified by cannulating the portal vein and thoracic duct of normal dogs and measuring the appearance of 14C labeled lipid, and 125I-insulin after oral administration of lipossmes in which 14C lipid and 125I-insulin have been used in manufacture. The absorption of "cold" insulin in these vessels will be determined through solubilization of liposomes. Hepatic extraction of liposome-insulin will be determined by simultaneous cannulation of portal and hepatic veins, and a peripheral artery, measurements of blood flow via flowmeters, and differences in plasma concentrations of insulin. Since the composition and size of the particles significantly affect their distribution and fate in tissues, liver and muscle will be biopsied at intervals after administering oral liposome-insulin for light and electron microscopy. Finally, when optimal composition and size are known the efficacy and toxicity of frequent administration and long-term therapy in diabetic rats and dogs will be compared to stand insulin therapy. In preliminary studies we have incorporated insulin into liposomes and confirmed incorporation by RIA of insulin after treatment with Triton X-100, and obtained responses in diabetic rats.